SU1055105A1 - 4-adamantoylamind-3-adamantoyl-6-methyl-2-ethyl-pyridine hydrochloride displaying psychostimulating activity - Google Patents

Abstract

Hydrochloride C-adamantoylamino3-0-adamantoyl-6-methyl-2-ethylpyridine of the formula HC1 with psychostimulating activity, increasing physical performance and having anti-cataleptic activity. JV ate: l

Description

The invention relates to the chemical and pharmaceutical industry, namely to a new biologically active chemical compound exhibiting psychostimulating and anti-cataleptic activity, i.e. to N-, 0-diadamantyl derivative of A-amIno-6-methyl-3-hydroxy-2-ethylpyridine of formula

HCl

Adamantane derivatives are known to have psychostimulating activity, such as, for example, substituted N-adamantylaniline, substituted -alkyl, and N-acyl-1- and 2-amino-admantane, which exhibit anti-cataleptic properties. However, the well-known anti-Parkinsonian drug midantan with long-term use causes insomnia, increased irritability and aggressiveness in patients. A drug with such a psychostimulant profile can hardly be used in general medical practice.

Ukanny above N- (2-adamantyl) -aniline, along with psychostimulant action, has significant toxicity. In the medical practice of psychostimulating action, phenamine is used, which is considered one of the most active drugs of this type of action. Phenymin at a dose of 1-10 mg / kg increases physical performance in mice by 1.3 times, however, has a high toxicity of mg / kg (br) and a small breadth of therapeutic effect.

The antiparkinsonian effect manifests the currently used midantane (hydrochloride of 1-aminoadamantane), the disadvantages of which also include significant toxicity (270 mg / kg).

Among pyridine derivatives, a large number of physiologically active compounds are also known, including substances exhibiting psychotropic properties, for example, iprazide-2-isopropyl-1-isonicotinoyl hydrazide is an active inhibitor of monoamine oxidase, it is used to treat patients with mild and moderate depressed state. However, it is very toxic, has a side effect on the liver and other organs.

The aim of the invention is to expand the arsenal of means of action on a living organism from compounds of the row of substituted pyridine, which has a psychostimulatory effect, increases physical performance and has anti-parkin Sonic activity and has significantly less toxicity compared to known substances. The goal is achieved by a new 4-adamantaylamino 3-0-adamantoyl-6-methyl-2-ethylpyridine hydrochloride of formula

HC1

which has psychostimulating activity, increases physical performance and has anti-cataleptic activity ..

This compound is a white crystalline substance with a mp. ZIZ-ZI C, soluble in ethanol. In the infrared spectrum of the base, taken up in chloroform, there are characteristic carbonyl absorption bands of the amide group at 1b95, vibrations of the ester group carbonyl occur at 1755 cm. The absorption band of the NH group is found in the region of cm.

This compound is obtained by known acylation of the hydroxy and amino groups, i.e. under the action of 1-adamantanecarboxylic acid chloride on α-amino-6-methyl-3 hydroxy-2-ethklipisidine in toluene in the presence of triethylamine, followed by treatment of the base obtained with an alcoholic solution of hydrogen chloride.

Primer p. Preparation of 4-adamantoylamino-3-O-adamantoyl-6 methyl-2-ethylpyridine hydrochloride.

To a suspension of 1.52 g (0.01 mol) -amino-6-methyl-3-hydroxy-2-ethylpyridine in 50 ml of dry doluene with stirring and add 2.75 ml of dry triethylamine. The reaction mass is cooled to 20–25 ° and a solution of 3, S7 (0.02 mol) 1-adamantanecarboxylic acid chloride in 15 ml of dry toluene is slowly dripped into drops.

The reaction mass is stirred at 25-30 ° C for 4.5 hours. The precipitate of triethylamine hydrochloride is filtered off, washed with ml of dry toluene. The toluene solution is evaporated, the residue is dissolved in chloroform. The chloroform solution is washed with 20 ml of a 5% aqueous alkali solution and then with water until neutral. Dry b / w with magnesium sulfate, and then evaporate to dryness. The residue was dissolved in absolute ethanol, and a solution of hydrogen chloride was added to pH 2-3. The precipitate was filtered off and washed with ether. Yield 2.8 g (5.60). White crystals with so pl. 212-21 | C (decomp., From absolute ethanol).

Found: C 70.5; H 7.9, C1 7, M N5.7.

C ffVN OjHC1

Calculated,%: C, 70.2; H, 8.1; C1 6.9, N 5.5.

The resulting compound has a pronounced psychostimulating effect, while the strength of the anti-cataleptic effect is much superior to anthrax and phenamine with significantly less toxicity. Comparative data is shown in the table. Thus, the introduction of two adamantoyl groups into the oxyaminopyridine derivative leads to the creation of a biologically active compound that has low toxicity and enhances physical performance, relieves catalepsy in parkinson's disease, and has a psychostimulating effect.

1 mg / kg Physical performance level (change in to 10 mg / kg control) 1 mg / kg Spontaneous motor activity (changes of 10 mg / kg compared to control) 1 mg / kg Body temperature change,% (relative to control) 5 mlg / kg kQ Anti-cataleptic activity (% withdrawal of 100% catalepsy with the administration of 2 mg / kg of triftazine) Acute daily toxicity 3000 mg / kg of LDDD 26 (in none 4, Tzo% enamine 1 mg / kg 10 mg / kg enamine 1 mg / kg 10 mg / kg (depression) Namin 1 mg / kg idantan 5 mg / kg enamine 13 mg / kg bo / id idantan 270 mg / kg i / br

Claims (1)

<claim-text> <table border = "1"> <tbody> <tr> <td> Test </ td> <td colspan = "2"> Claimed compound and its dose </ td> <td colspan = "3"> Analogue and its dose of '</ td> </ tr> <tr> <td> Level of physical performance </ td> <td> 1 mg / kg </ td> <td> 125% </ td> <td> phenamine </ td> <td> 1 mg / kg </ td> <td> tzo% · </ td> </ tr> <tr> <td> (change in% of control) </ td> <td> 10 mg / kg </ td> <td> 74% </ td> <td> </ td> <td> 10 mg / kg </ td> <td> 139% </ td> </ tr> <tr> <td> Spontaneous activity </ td> <td> 1 mg / kg </ td> <td> 132% </ td> <td> phenamine </ td> <td> 1 mg / kg </ td> <td> 156% </ td> </ tr> <tr> <td> (% change compared to control) </ td> <td> 10 mg / kg </ td> <td> 261% (oppression) </ td> <td> </ td> <td> 10 mg / kg </ td> <td> 473% (oppression) </ td> </ tr> <tr> <td> Changes in body temperature,% (relative to control) </ td> <td> 1 mg / kg </ td> <td> 4.28% </ td> <td> phenamine </ td> <td> 1 mg / kg </ td> <td rowspan = "2"> 93% </ td> </ tr> <tr> <td> Anti-cataleptic activity (% withdrawal 100% catalepsy with the introduction of 2 mg / kg of triftazina) </ td> <td> 5 mlg / kg </ td> <td> 40% </ td> <td> Midantan </ td> <td> 5 mg / kg </ td> </ tr> <tr> <td> Acute daily toxic - </ td> <td> w / br </ td> <td> </ td> <td> phenamine </ td> <td> 13 mg / kg </ td> <td> b / c </ td> </ tr> <tr> <td> nuance nuclear 50 </ td> <td> 3000 mg / kg </ td> <td> </ td> <td> Midantan </ td> <td> 270 mg / kg </ td> <td> b / c </ td> </ tr> </ tbody> </ table>